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A group of new studies on the genetics of epileptic encephalopathy (EE) — a severe group of epilepsies characterized by refractory seizures and cognitive arrest or regression, associated with ongoing epileptic activity, that typically carry a poor prognosis — is making it clear just how complex the etiology of this disorder is. Emerging from these studies are new genes, new pathways, and new appreciation for the overlap of EE with other neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability.

Heather Mefford, MD, PhD, assistant professor of pediatrics at the University of Washington in Seattle, looks for gene mutations using “next generation” sequencing, a technique that allows probing many genes at once.

In a new study presented last month at the American Epilepsy Society meeting in Washington, DC, Dr. Mefford reported the results of this approach in over 600 EE patients, screening for mutations in over 100 genes. The work expanded on her study of more than 500 patients and over 60 genes, published Sept. 12 in Nature Genetics.

“Traditionally — five years ago — sequencing was done on one gene at a time, one exon at a time,” Dr. Mefford explained. While next-generation sequencing is still a long way from sequencing the entire genome, “it allows us to cherry pick sequences for genes we want to study. We can pull out the coding regions of all those genes, and sequence them all at once.”

She chose to look at several classes of genes: genes previously known to cause epilepsy, in order to look at the associated phenotypic spectrum; genes associated with intellectual disability or ASD; and genes she suspected were associated with epilepsy but had never been confirmed as causative.

Overall, she found likely or confirmed disease-causing mutations in 10 percent of the patients. About 15 percent of candidate genes tested that were not previously associated with epilepsy carried likely causative mutations. Three new genes were responsible for disease in more than one patient: chromodomain-helicase-DNA-binding protein 2 (CHD2), synaptic Ras GTPase-activating protein 1 (SYNGAP1), and myocyte-specific enhancer factor 2C (MEF2C).

“It [CHD2] is becoming an important gene family,” Dr. Mefford said, “since it gives a new pathway for understanding neurodevelopmental disorders.” A recent study from a European consortium found CHD2 mutations in Dravet syndrome patients without sodium channel mutations, and confirmed its pathogenicity in a zebrafish disease model. Dravet syndrome is a form of EE, characterized by febrile seizures and risk of status epilepticus.

A smaller number of patients in her study carried mutations in MEF2C, another developmental regulatory gene associated with autism. SYNGAP1 is involved in synapse formation, and has previously been implicated in intellectual disability.

The genetic connections and clinical overlap among these neurodevelopmental disorders “is an emerging theme,” Dr. Mefford said, likely due to pleiotropic effects of these genes during development. But not every mutation is associated with such a wide phenotypic spectrum. In her newest study, she found that mutations in GRIN2A, a glutamate receptor subunit, are restricted to epilepsy aphasia syndromes, and mutations in GABRA1, a GABA receptor subunit, are linked only to Dravet syndrome.

“We are finding that there is a lot of genetic heterogeneity in epileptic encephalopathy, probably in part due to the complexity of brain development, and the number of genes involved,” she said. “Little by little, we are getting better at being able to diagnose patients, as we identify these new genetic causes, but I think we are still really at the tip of the iceberg. This is telling us we have a lot more gene discovery to do.”

That complexity also argues for sequencing many genes simultaneously in looking for a diagnosis for most individual epilepsy patients, she said. “It is hard to guess when the patient walks in the door which mutation they are going to have, and therefore which genes to test.”